6-substituted amino-3-cyanoquinoline compounds (compounds of formula A) are important pharmaceutical intermediates. They also are key intermediates for preparing 3,4-disubstituted quinoline compounds.

For example, 6-substituted amino-4-hydroxy-3-cyanoquinoline (compounds A1) and 6-substituted amino-4-chloro-3-cyanoquinoline (compounds A2) are important intermediates for preparing compound HKI-272. The compound HKI-272 is an irreversible small molecular tyrosine kinase inhibitor (Journal of Medicinal Chemistry, 46(1):49-63) useful for treating Colorectal cancer, Breast cancer, non-small-cell lung cancer, and has entered into clinic trial phase, being most likely to become a new anticancer drug with a promising market. Therefore, it is of great practical value to optimize the synthetic process of compounds A.

The key step to prepare compounds A is the formation of a quinoline ring, which usually requires a high temperature condition. For example, compound B is heated at 240-260° C. for 10-20 h in high boiling point solvents (scheme 1) (WO03093241, US2005065181, CN101012225). The reaction condition is much rigorous, and the high temperature may cause decomposition of the product, increase of by-products and low purity of product. Thus, this step has a low yield of only about 40%. Furthermore, the high boiling point solvents such as Dowtherm A are volatilized at the high temperature, which has inevitably an adverse affect on the work environment and the health of the operator, and pollution of the environment. Therefore, there is an urgent need to develop an improvement preparation method possessing mild reactive condition, high yield, little pollution to the environment, and being suitable for industry production.
